Welcome to 3FF3! Bio-organic Chemistry - Harjono

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Nov 15, 2013 (3 years and 6 months ago)

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Bio
-
organic
Chemistry

Dr.
Supartono
, M.S.

Harjono
,
S.Pd
.
M.Si
.

What is bio
-
organic chemistry? Biological
chem
?
Chemical bio?

Chemical Biology
:


“Development & use of chemistry techniques for the study of
biological phenomena” (Stuart Schreiber)

Biological Chemistry
:


“Understanding how biological processes are controlled by
underlying chemical principles” (
Buckberry

& Teasdale)

Bio
-
organic Chemistry
:


“Application of the tools of chemistry to the
understanding of biochemical processes” (
Dugas
)


What’s the difference between these???

Deal with interface of biology & chemistry

BIOLOGY

CHEMISTRY

Simple organics


eg

HCN, H
2
C=O

(mono
-
functional
)

Biologically relevant organics:
polyfunctional

Life

large macromolecules;
cells

contain
~ 100,
000 different
compounds interacting

1
°

Metabolism


present in all cell




2
°

Metabolism


specific species,
eg
.
Caffeine

CHEMISTRY:

Round
-
bottom flask

BIOLOGY:

cell

How different
are they?

Exchange of ideas:


Biology




Chemistry



Chemistry explains events of biology:


mechanisms, rationalization



Biology


Provides challenges to chemistry:

synthesis,
structure determination



Inspires chemists:
biomimetics

→ improved chemistry
by understanding of biology (e.g. enzymes)

Key Processes of 1
°

Metabolism

Bases + sugars
→ nucleosides


nucleic acids


Sugars (monosaccharides)


polysaccharides


Amino acids proteins


Polymerization reactions; cell also needs the reverse process


We will look at each of these 3 parts:


1)
How do chemists synthesize these structures?

2)
How are they made in vivo?

3)
Improved chemistry through understanding the biology:
biomimetic synthesis

Properties of Biological Molecules that Inspire
Chemists

1)
Large
→ challenges:






for synthesis



for structural prediction (e.g. protein folding)


2)

Size → multiple FG’s (active site) ALIGNED to achieve a
goal



(e.g. enzyme active site, bases in NAs)


3)

Multiple non
-
covalent weak interactions → sum to strong,
stable binding non
-
covalent complexes



(e.g. substrate, inhibitor, DNA)


4)

Specificity → specific interactions between 2 molecules in
an ensemble within the cell





5) Regulated → switchable, allows control of cell →
activation/inhibiton


6) Catalysis
→ groups work in concert


7) Replication → turnover



e.g. an enzyme has many turnovers, nucleic acids
replicates

Evolution of Life


Life did not suddenly crop up in its element form of complex
structures (DNA, proteins) in one sudden reaction from mono
-
functional simple molecules

In this course, we will follow some of the ideas of how life may
have evolved:


HCN + NH
3
bases
H
2
C=O
sugars
nucleosides
phosphate
nucleotides
RNA
"RNA world"
catalysis
more RNA, other
molecules
modern "protein" world
CH
4
, NH
3
H
2
O
amino
acids
proteins
RNA
(ribozyme)
RNA World


Catalysis by
ribozymes

occurred
before

protein catalysis


Explains current central dogma:






Which came first: nucleic acids or protein?



RNA world hypothesis suggests RNA was first molecule
to act as both template & catalyst:



catalysis

&
replication

DNA
transcription
RNA
protein
translation
requires
protein
requires RNA
+ protein
How did these reactions occur in the pre
-
RNA world? In the
RNA world? & in modern organisms?


CATALYSIS & SPECIFICITY


How are these achieved? (Role of NON
-
COVALENT
forces


BINDING)


a) in chemical synthesis


b) in vivo


how is the cell CONTROLLED?


c) in chemical models


can we design better chemistry
through understanding biochemical mechanisms?

Relevance of Labs to the Course

Labs illustrate:


1)
Biologically relevant small molecules (e.g. caffeine
)

2)
Structural principles & characterization



(e.g.
anomers

of glucose,
anomeric

effect,

diastereomers
,
NMR)

3)
Cofactor chemistry


pyridinium

ions (e.g.
NADH)

4)
Biomimetic

chemistry (e.g. simplified model of
NADH)

5)
Chemical mechanisms relevant to
catalysis (
e.g.
NADH)

6)
Application of biology

to
stereoselective

chemical
synthesis (e.g.
yeast)

7)
Synthesis of small molecules


(e.g. drugs,
dilantin
,
tylenol
)

8)
Chemical catalysis (e.g. protection & activation
strategies relevant to peptide synthesis in vivo and in
vitro)


All of these demonstrate inter
-
disciplinary area between
chemistry & biology


Two Views of DNA


1)
Biochemist’s view:





shows overall shape, ignores atoms & bonds


2)
chemist’s view: atom
-
by
-
atom



structure, functional
groups

Biochemist’s View of the DNA Double Helix

Major
groove

Minor
groove

N
N
H
O
O
O
H
O
H
H
O
H
H
H
O
P
O
O
O
H
H
O
P
O
O
O
2
o
alcohol
(FG's)
alkene

bonds
resonance
Ring
conformation
ax/eq
H-bonds
nucleophilic
electrophilic
substitution rxn
chirality

+


diastereotopic
Chemist’s View

BASES

N
N
pyridine
pyrrole

Aromatic structures:


all sp
2

hybridized atoms (
6 p orbitals, 6
π

e
-
)



planar (like benzene)



N has lone pair in both pyridine & pyrrole


basic
(H
+
acceptor or e
-

donor)


ArN:
H
+
ArNH
+
pKa?
N
H
N
H
H
+
+
6
π

electrons, stable cation


weaker
acid, higher pKa (~ 5) & strong conj.
base

sp
3

hybridized N, NOT aromatic


strong acid, low pKa (
~
-
4) & weak conj.
base


Pyrrole uses lone pair in aromatic sextet → protonation
means loss of aromaticity (BAD!)


Pyridine’s N has free lone pair to accept H+




pyridine is often used as a base in organic chemistry, since it
is soluble in many common organic solvents


The lone pair also makes pyridine a H
-
bond acceptor
e.g. benzene is insoluble in H
2
O but pyridine is soluble:










This is a NON
-
specific interaction, i.e., any H
-
bond donor
will suffice








N
H
O
H
:
e
-
donor
e
-
acceptor
H-bond
acceptor
H-bond
donor
acid
base
Contrast with Nucleic Acid Bases

(A, T, C, G, U)


Specific!

N
N
N
N
N
H
2
H
N
N
N
N
O
N
H
2
H
N
N
H
O
O
H
N
N
H
O
O
H
N
N
O
N
H
2
H
Thymine (T)
Guanine (G)
Adenine (A)
Uracil (U)
Cytosine (C)
*
*
*
*
*
Pyrimidines (like pyridine):
Purines
(DNA only)
(RNA only)
* link to sugar

Evidence for specificity?


Why are these interactions specific?

e.g. G
-
C & A
-
T



Evidence?


If mix G & C together

exothermic reaction occurs; change in
1
H
chemical shift in NMR; other changes


reaction

occurring


Also occurs with A & T


Other combinations
→ no change!


N
H
N
N
N
O
N
H
H
H
N
H
N
O
N
H
H
G
C
2 lone pairs
in
plane
at 120
o
to
C=O bond
e.g. Guanine
-
Cytosine:


Why?


In G
-
C duplex, 3 complementary H
-
bonds can form: donors &
acceptors =
molecular recognition



Can use NMR to do a titration curve:









Favorable reaction because
Δ
H for complex formation =
-
3 x H
-
bond energy


Δ
S is unfavorable → complex is organized







3 H
-
bonds overcome the entropy



of complex formation



**Note: In synthetic DNAs other interactions can occur

G + C
K
a
G C
get equilibrium constant,

G = -RT ln K =

H-T

S

Molecular recognition not limited to natural bases:





Create new architecture
by thinking about biology i.e.,
biologically inspired
chemistry!

Forms supramolecular
structure: 6 molecules in a
ring

Synthesis of Bases (Nucleic)


Thousands of methods in heterocyclic chemistry


we’ll
do 1 example:





May be the first step in the origin of life…









Interesting because H
-
CN/CN
-

is probably the simplest molecule
that can be both a nucleophile & electrophile, and also form C
-
C
bonds

N
H
N
N
N
N
H
2
NH
3
+
HCN
Adenine
Polymerization of HCN
Mechanism?

C
N
N
H
H
+
N
H
N
H
N
H
N
N
H
H
N
H
C
N
N
H
H
N
H
N
H
N
H
+
N
H
N
N
N
H
N
H
N
H
H
+
N
N
N
N
H
N
H
2
N
H
3
H
+
N
N
N
N
N
H
2
H
H
H
H
+
N
N
N
H
N
N
H
2
H
H
+
tautomerization
N
N
H
3
N
N
N
H
HC
G, U, T and C
(cyanogen)
(cyanoacetylene)
Other Bases?

**
Try these mechanisms!

Properties of Pyridine



We’ve seen it as an acid & an H
-
bond acceptor


Lone pair can act as a nucleophile:








N
R
X
N
+
R
N
X
O
N
O
+
S
N
2
+
+
N
O
N
H
2
P
h
N
O
N
H
2
P
h
N
O
N
H
2
P
h
H
H
+
+
aromatic, but
+ve charge
electron acceptor:
electrophile
"H
-"
reduction
(like NaBH
4
)
e.g. exp 3: benzyl dihydronicotinamide

Balance between aromaticity & charged vs non
-
aromatic
& neutral!




can undergo REDOX reaction reversibly:



NAD-H
NAD
+
+ "H
-
"
reductant
oxidant

Interestingly, nicotinamide may have been present in the
pre
-
biotic world:












NAD or related structure may have controlled redox
chemistry long before enzymes involved!


N
H
C
N
N
H
C
N
N
N
H
2
O
Diels-
Alder
[O],
hydrolysis of CN
1% yield
electical
discharge

CH
4

+ N
2

+ H
2

Another example of
N
-
Alkylation of Pyridines

N
H
N
N
N
H
O
O
N
N
N
N
H
O
O
C
H
3
Caffeine
This is an S
N
2 reaction with stereospecificity

R
N
H
R
C
H
3
S
+
Met
A
d
R
N
R
C
H
3
S
Met
A
d
+
+
s-adenosyl methionine
References

Solomons


Amines: basicity ch.20


Pyridine & pyrrole pp 644
-
5


NAD
+
/NADH pp 645
-
6, 537
-
8, 544
-
6


Bases in nucleic acids ch. 25


Also see Dobson, ch.9


Topics in Current Chemistry, v 259, p 29
-
68